Finished Pharmaceutical Dosage Form Of A Methenamine Salt Such As Methenamine Mandelate

ABSTRACT

The present invention contemplates a high dose finished pharmaceutical dosage form comprising a methenamine salt, such as methenamine mandelate, as an active pharmaceutical ingredient wherein the methenamine salt API has a moisture content that is less than the upper limit specified in the USP. A preferred embodiment of the present invention has a moisture content that is half of the limit set forth in the USP for each particular methenamine salt. An even more preferred embodiment has a moisture content of less than or equal to one-tenth of a percent (0.1%), regardless of the methenamine salt. The present invention may include one or more pharmaceutically acceptable ingredients. The present invention also contemplates a moisture content of the high dose finished pharmaceutical dosage form that is less than one percent.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of International ApplicationNo. PCT/US2020/031459, filed on May 5, 2020, which claims priority toU.S. patent application Ser. No. 16/705,414, filed on Dec. 6, 2019, thedisclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The use of active pharmaceutical ingredients (“APIs” or in the singularform “API”) that have chemical reactivity in water in high dose tabletdosage forms where the API comprises the majority of the pharmaceuticalformulation (defined as 75% w/w or more of API in a single tablet) ischallenging for pharmaceutical formulation scientists. These high dosetablet dosage forms are challenging because (1) the compactionproperties of the API are critical to the formation of a robust tabletdosage form, (2) the small quantity of excipient(s) per tablet makes itdifficult to get suitable compression, and (3) the chemical reactivityof certain APIs makes common processing techniques for ordinary highdose tablet dosage forms unacceptable. A person of skill in the artunderstands that an excipient is an inert ingredient that is acceptablefor use in a finished pharmaceutical dosage form.

For high dose tablet dosage forms, it is common to use the wetgranulation processing technique to impart suitable compactionproperties to the mixture of the active pharmaceutical ingredient(s) andthe excipient(s). A person of skill in the art understands that wetgranulation creates an intimate mixture of the pharmaceuticalformulation ingredients that promote both improved flow and compactionproperties thereby modifying the properties of the API to the greatestextent of any of the pharmaceutical processing techniques. Wetgranulation often utilizes binder solutions to wet mass the formulationmixture creating, in many cases, API particles with binder on thesurface of each secondary particle, so during compaction it is thebinder material that makes direct contact with other binder material toform the finished tablet dosage form. These secondary API particlescomprised not only of API, but of the formulation mixture, willdemonstrate improved compaction properties. As defined above for highdose tablet dosage forms, the formulation mixture of the activepharmaceutical ingredient(s) and the excipient(s) contains a higherpercentage of the active pharmaceutical ingredient(s), typically 75% w/wor more, when compared to the percentage of excipient(s); thus, wetgranulation is particularly valuable to impart suitable compactionproperties and form satisfactory finished tablet dosage forms. Foractive pharmaceutical ingredient(s) with sensitivity to water, however,typical aqueous-based wet granulation may not be an option because wetgranulation will expose the API(s) to water.

Even direct compression, also known to the those in the art as dry blendprocessing, can present challenges when dealing with APIs that havechemical reactivity in water in high dose tablet dosage forms. Withoutthe ability to modify the compaction properties of the API using wetgranulation, the flow and compaction properties of the neat API becomecritical to the formation a robust tablet dosage form.

In direct compression, the residual moisture content of the final blend(or in the case of a high dose tablet dosage form, the moisture contentof the API itself) must be considered and increasing this moisturecontent is typically used to improve the compaction properties of thefinal blend. For APIs that are sensitive to water, however, increasingmoisture content is not suitable because it can result in degradation ofthe API. On the other hand, a simple reduction in moisture content ofthe API to reduce the chemical reactivity or degradation can also becounterproductive to the formation/compaction of the high dose tabletdosage form, which is why formulating a high dose tablet dosage formwith an API that is sensitive to water can be a significant challenge toa pharmaceutical formulation scientist.

Methenamine salts (including mandelate and hippurate salt forms) are anexample of APIs that have the abovementioned chemical reactivity inwater. Methenamine salts act as urinary antibacterial agents that reactin acidic aqueous medium to form ammonia and the antibacterial agent,formaldehyde. The therapeutic activity of methenamine salts alsorequires a high dosage in order to be effective. Commercially availabletablets containing methenamine salts are available in 500 mg and 1,000mg formulations. The mechanism of action of methenamine saltsillustrates why the water content in a high dose tablet dosage form of amethenamine salt is critical. For the avoidance of doubt, themethenamine salts react in an aqueous media, so controlling the amountof water in the dosage form protects the methenamine salt from reactingwith the residual water. Because the sensitivity to water is only aconcern for the methenamine moiety, a formulation of any salt form ofmethenamine (including mandelate and hippurate) faces the same challengewith respect to water content. For ease of discussion, thisspecification focuses on methenamine mandelate, but a person of skill inthe art understands that the concepts herein apply to any salt form ofmethenamine.

Following administration as a pharmaceutical tablet dosage form,methenamine mandelate is rapidly absorbed (as methenamine and mandelicacid) and excreted by the kidney to concentrate in the urine. Theantibacterial therapeutic activity is primarily the result of hydrolysisof the methenamine moiety, which is maximized at a pH of 5.5 or less inthe urine. Mandelic acid also provides antibacterial activity, and itaids in the effectiveness of the methenamine moiety because the mandelicacid acidifies a patient's urine. While the normal range for urine pH is4.6-8.0 depending on the materials excreted by the kidney, the presenceof mandelic acid will lower the pH of a patient's urine, which enhancesthe effectiveness of the methenamine moiety.

The symbiosis of the methenamine moiety and mandelic acid poses achallenge to the pharmaceutical scientist. Methenamine mandelate, likeany other API, has an inherent moisture content as a bulk drugsubstance. In the micro environment surrounding each API crystal, themoisture/water present in the API is, in fact, a saturated solution ofboth methenamine and mandelic acid providing an ideal environment forhydrolysis or drug degradation. Controlling the water content of the APIthus helps to prevent hydrolysis or drug degradation and this is validfor both the bulk drug substance and in the finished tablet dosage form.

The United States Pharmacopeia (USP) sets limits for moisture content ofAPIs. The USP monograph for methenamine mandelate establishes aspecification of less than 1.5% moisture content using the generalphysical USP test, Loss on Drying <731>. The USP monograph formethenamine hippurate establishes a specification of less than 1.0%moisture content using the general physical USP test, Loss on Drying<731>. Controlling the water content to a specification lower than thelimit specified in the USP results in a finished dosage product withless hydrolysis, which in turn decreases the potential for drugdegradation and improves the shelf life of the finished dosage product.

BRIEF SUMMARY OF THE INVENTION

The present invention contemplates a high dose finished pharmaceuticaldosage form comprising a methenamine salt, such as methenaminemandelate, as an active pharmaceutical ingredient wherein themethenamine salt API has a moisture content that is less than the upperlimit specified in the USP. The present invention may include one ormore pharmaceutically acceptable excipients. The present inventionbalances the need to keep moisture content low, for both the API and theresulting finished tablet dosage form, to prevent drug degradation andthe need to have a drug product blend that can be compressed into thedesired finished tablet dosage form.

A drug product formulation of a methenamine salt (e.g., methenaminemandelate) is disclosed in greater detail below. The present inventionincludes a drug product comprising an methenamine salt with a moisturecontent that is significantly lower than is allowed by the USP thatstill has suitable compaction properties resulting in a finished tabletdosage form that is viable for commercial manufacturing.

DETAILED DESCRIPTION OF THE INVENTION

The present invention contemplates a high dose finished pharmaceuticaldosage form comprising a methenamine salt, such as methenaminemandelate, as an active pharmaceutical ingredient wherein themethenamine salt API has a moisture content that is less than the upperlimit specified in the USP. A preferred embodiment of the presentinvention has a moisture content that is half of the limit set forth inthe USP for each particular methenamine salt. An even more preferredembodiment has a moisture content of one-tenth of a percent (0.1%),regardless of the methenamine salt. Preferred embodiments of the presentinvention include tablet dosages that contain either 500 milligrams or1,000 milligrams of a methenamine salt per tablet where the APIcomprises 75% w/w or more of the finished dosage form, but any amount ofmethenamine salt is included within this invention.

The present invention may include one or more pharmaceuticallyacceptable ingredients. The types pharmaceutically acceptable excipientswould be understood by a person of skill in the art. Some types ofexcipients that may be used include diluents/binders/fillers,disintegrants, glidants, and lubricants. Exemplarydiluents/binders/fillers include starch, microcrystalline cellulose,hydroxypropyl cellulose, povidone, lactose, and dicalcium phosphate.Exemplary disintegrants include starch, croscarmellose sodium, sodiumstarch glycolate, and cross-linked polyvinyl pyrrolidone. Exemplaryglidants include silicas and talc. Exemplary lubricants include stearicacid, magnesium stearate, and sodium stearyl fumarate.

The reactivity of the methenamine salts in water form, as describedabove, the basis for the finished dosage product's therapeutic activity,but it is also the basis for concern in drug degradation over the shelflife of the finished tablet dosage form. Beyond controlling the moisturecontent of the API, the present invention seeks to control the moisturecontent of the finished dosage form because the water resulting fromother ingredients or the process can also cause drug degradation. Apreferred embodiment of the finished pharmaceutical dosage form also hasa moisture content of less than 1.0 percent.

A person of skill in the art understands that reducing the moisturecontent of the API used in the finished tablet dosage form can havenegative effects in terms of processing and compaction of the finishedtablet dosage form. Reducing the moisture content of the API or thefinished dosage product is not a practical solution if a finished tabletdosage form cannot be made, e.g., if the low moisture formulation(s)cannot be compressed into a finished tablet dosage form. One criticalaspect of this invention is the balance between using a high dose APIwith a low moisture content specification and designing a suitablepharmaceutical tablet formulation. This balance is not presented in theprior art and would not be apparent to a person of skill in the art.

The following examples are provided to help understand the invention butare not intended to limit the scope of the invention.

Example 1

The formula and process of one exemplary embodiment of the presentinvention is described below.

Mg/tablet Percent (%) Active Pharmaceutical Ingredient Methenaminemandelate 1000.0 75.00 Excipients Microcrystalline cellulose 50 μm 320.024.00 Magnesium stearate 13.3 1.00 Total 1333.3 100.00

The first two materials (methenamine mandelate and microcrystallinecellulose 50 μm) are charged into a v-blender. The materials are mixeduntil sufficiently dispersed. The magnesium stearate is passed through a40 mesh screen and pre-blend with a small portion of the blendedmaterials in the v-blender. Add pre-blend to remaining materials in thev-blender and mix until adequately dispersed. The final blend isdischarged from the blender and charged into the hopper of a tabletpress to compact into finished tablet dosage forms.

320.0 milligrams of microcrystalline cellulose 50 μm was added in thisexample. For a tablet with 1,000 mg of API such as the tablet in Example1, the amount of this excipient could range from 200 to 350 milligrams.13.3 milligrams of magnesium stearate was added in this example. For atablet with 1,000 mg of API such as the tablet in Example 1, the amountof this excipient could range from 7 to 25 milligrams.

Example 2

The formula and process of another exemplary embodiment of the presentinvention is described below.

Mg/tablet Percent (%) Active Pharmaceutical Ingredient Methenaminemandelate 500.0 80.00 Excipients Microcrystalline cellulose 50 μm 119.019.04 Magnesium stearate 6.0 .96 Total 625.0 100.00

The first two materials (methenamine mandelate and microcrystallinecellulose 50 μm) are charged into a v-blender. The materials are mixeduntil sufficiently dispersed. The magnesium stearate is passed through a40 mesh screen and pre-blend with a small portion of the blendedmaterials in the v-blender. Add pre-blend to remaining materials in thev-blender and mix until adequately dispersed. The final blend isdischarged from the blender and charged into the hopper of a tabletpress to compact into finished tablet dosage forms.

119.0 milligrams of microcrystalline cellulose 50 μm was added in thisexample. For a tablet with 500 mg of API such as the tablet in Example2, the amount of this excipient could range from 75 to 150 milligrams.6.0 milligrams of magnesium stearate was added in this example. For atablet with 500 mg of API such as the tablet in Example 2, the amount ofthis excipient could range from 3 to 13 milligrams.

Example 3

The formula and process of another exemplary embodiment of the presentinvention is described below.

Mg/tablet Percent (%) Active Pharmaceutical Ingredient Methenaminemandelate 1000.0 86.22 Excipients Microcrystalline cellulose 50 μm 60.05.17 Microcrystalline cellulose 20 μm 60.0 5.17 Hydroxypropyl cellulose20.0 1.72 Magnesium stearate 20.0 1.72 Total 1160.0 100.00

The first four materials (methenamine mandelate, microcrystallinecellulose 50 .mu.m, microcrystalline cellulose 20 .mu.m, andhydroxypropyl cellulose) are charged into a v-blender. The materials aremixed until sufficiently dispersed. The magnesium stearate is passedthrough a 40 mesh screen and pre-blended with a small portion of theblended materials in the v-blender. Add pre-blend to remaining materialsin the v-blender and mix until adequately dispersed. The final blend isdischarged from the blender and charged into the hopper of a tabletpress to compact into finished tablet dosage forms.

60.0 milligrams of microcrystalline cellulose 50 .mu.m was added in thisexample. For a tablet with 1,000 mg of API such as the tablet in Example3, the amount of this excipient could range from 10 to 110 milligrams.60.0 milligrams of microcrystalline cellulose 20 .mu.m was added in thisexample. For a tablet with 1,000 mg of API such as the tablet in Example3, the amount of this excipient could range from 10 to 110 milligrams.20.0 milligrams of hydroxypropyl cellulose was added in this example.For a tablet with 1,000 mg of API such as the tablet in Example 3, theamount of this excipient could range from 5 to 50 milligrams. 20.0milligrams of magnesium stearate was added in this example. For a tabletwith 1,000 mg of API such as the tablet in Example 3, the amount of thisexcipient could range from 6 to 24 milligrams.

Example 4

The formula and process of another exemplary embodiment of the presentinvention is described below.

Mg/tablet Percent (%) Active Pharmaceutical Ingredient Methenaminemandelate 1000.0 83.32 Excipients Microcrystalline cellulose 50 μm 60.05.00 Microcrystalline cellulose 20 μm 60.0 5.00 Hydroxypropyl cellulose26.0 2.17 Sodium Starch Glycolate 26 2.17 Colloidal Silicon Dioxide 80.67 Magnesium stearate 20 1.67 Total 1200.0 100.00

The first five materials (methenamine mandelate, microcrystallinecellulose 50 .mu.m, microcrystalline cellulose 20 .mu.m, hydroxypropylcellulose, and sodium starch glycolate) are charged into a v-blender.The materials are mixed until sufficiently dispersed. The colloidalsilicon dioxide and magnesium stearate are passed through a 40 meshscreen and pre-blended with a small portion of the blended materials inthe v-blender. Add pre-blend to remaining materials in the v-blender andmix until adequately dispersed. The final blend is discharged from theblender and charged into the hopper of a tablet press to compact intofinished tablet dosage forms.

60 milligrams of microcrystalline cellulose 50 .mu.m was added in thisexample. For a tablet with 1,000 mg of API such as the tablet in Example4, the amount of this excipient could range from 10 to 110 milligrams.60 milligrams of microcrystalline cellulose 20 .mu.m was added in thisexample. For a tablet with 1,000 mg of API such as the tablet in Example4, the amount of this excipient could range from 10 to 110 milligrams.26 milligrams of hydroxypropyl cellulose was added in this example. Fora tablet with 1,000 mg of API such as the tablet in Example 4, theamount of this excipient could range from 5 to 50 milligrams. 26milligrams of sodium starch glycolate was added in this example. For atablet with 1,000 mg of API such as the tablet in Example 4, the amountof this excipient could range from 6 to 44 milligrams. 8 milligrams ofcolloidal silicon dioxide was added in this example. For a tablet with1,000 mg of API such as the tablet in this Example 4, the amount ofcolloidal silicon dioxide could range from 1 to 16 milligrams. 20milligrams of magnesium stearate was added in this example. For a tabletwith 1,000 mg of API such as the tablet in Example 4, the amount of thisexcipient could range from 6 to 24 milligrams.

1. A finished pharmaceutical dosage form comprising: a methenamine mandelate active pharmaceutical ingredient having a moisture content of no more than one-tenth of a percent by weight based on a total weight of the methenamine mandelate, the methenamine mandelate being present in an amount of at least about 75% by weight of the finished pharmaceutical dosage form, and the finished pharmaceutical dosage form having a total moisture content of less than one percent based on a total weight of the finished pharmaceutical dosage form.
 2. The finished pharmaceutical dosage form of claim 1, wherein the finished pharmaceutical dosage form is a tablet.
 3. The finished pharmaceutical dosage form of claim 1, wherein the active pharmaceutical ingredient is present in an amount of 500 mg.
 4. The finished pharmaceutical dosage form of claim 1, wherein the active pharmaceutical ingredient is present in an amount of 1000 mg.
 5. The finished pharmaceutical dosage form of claim 1, wherein the moisture content of the methenamine mandelate active pharmaceutical ingredient is measured by the general physical USP test, Loss on Drying <731>.
 6. A tablet comprising: at least one pharmaceutically acceptable excipient; and a methenamine salt active pharmaceutical ingredient having a moisture content of less than a moisture content specification set by the USP monograph for the methenamine salt, the methenamine salt being present in an amount of at least about 75% by weight of the finished pharmaceutical dosage form; the tablet having a total moisture content of less than one percent based on a total weight of the tablet.
 7. The tablet of claim 6, wherein the methenamine salt is methenamine mandelate having a moisture content of no more than one-tenth of a percent by weight based on a total weight of the methenamine mandelate.
 8. The tablet of claim 6, wherein the pharmaceutically acceptable excipient comprises a diluent, a binder, a filler, a disintegrant, a glidant, a lubricant, or any combination thereof.
 9. The tablet of claim 6, wherein the pharmaceutically acceptable excipient comprises starch, microcrystalline cellulose, hydroxypropyl cellulose, povidone, lactose, dicalcium phosphate, croscarmellose sodium, sodium starch, glycolate, cross-linked polyvinyl pyrrolidone, silica, talc, stearic acid, magnesium stearate, sodium stearyl fumarate, or any combination thereof.
 10. The tablet of claim 8, wherein the pharmaceutically acceptable excipient is a binder.
 11. The tablet of claim 8, wherein the pharmaceutically acceptable excipient is a lubricant.
 12. The tablet of claim 8, wherein the pharmaceutically acceptable excipient is a binder or a lubricant.
 13. The tablet of claim 6, wherein the active pharmaceutical ingredient is present in an amount of 500 mg.
 14. The tablet of claim 6, wherein the active pharmaceutical ingredient is present in an amount of 1000 mg.
 15. The tablet of claim 7, wherein the moisture content of the methenamine mandelate is measured by the general physical USP test, Loss on Drying <731>.
 16. A process of making a high dose tablet of methenamine mandelate comprising: providing 500 or 1,000 milligrams of methenamine mandelate having a reduced moisture content of 0.1% or less; blending the methenamine mandelate with a sufficient amount of at least one pharmaceutically acceptable excipient so as to form a tablet comprised of at least about 75% methenamine mandelate by weight of the tablet to form a blend, and compressing the blend into a tablet with a total moisture content of less than 1%.
 17. The process of claim 16, wherein the pharmaceutically acceptable excipient comprises starch, microcrystalline cellulose, hydroxypropyl cellulose, povidone, lactose, dicalcium phosphate, croscarmellose sodium, sodium starch, glycolate, cross-linked polyvinyl pyrrolidone, silica, talc, stearic acid, magnesium stearate, sodium stearyl fumarate, or any combination thereof.
 18. A tablet of 500 mg methenamine mandelate made by the process of claim
 16. 19. A tablet of 1,000 mg methenamine mandelate made by the process of claim
 16. 